Ezhuthachan College of Pharmaceutical Sciences, Marayamuttom, Neyyattinkara, Thiruvananthapuram.
Deep vein thrombosis (DVT) refers to the formation of a blood clot within the deep venous system, most commonly affecting the lower limbs. It is a potentially serious condition due to the risk of clot dislodgement leading to pulmonary embolism (PE). Hormonal agents, particularly progestogens like norethisterone, are known to carry a thrombotic risk, though such events remain relatively uncommon. This case report focuses on a 49-years-old female with abnormal uterine bleed who developed drug-induced deep vein thrombosis after being treated with norethisterone (15mg) twice daily for seven days and once daily for next seven days. The patient, with no significant prior history of thromboembolic events, commenced norethisterone therapy and subsequently presented with edema, pain, and swelling of the left lower limb. Doppler ultrasonography confirmed the diagnosis of extensive lower limb DVT. Norethisterone is a synthetic progestogen (a derivative of 19-nortestosterone) widely used in clinical practice for the management of various gynecological disorders. It exerts its action by mimicking the effects of natural progesterone, leading to endometrial transformation and suppression of ovulation at higher doses. It is prescribed to treat conditions such as abnormal uterine bleeding, menorrhagia. While hepatotoxicity is a known side effect, it is rarely associated with a hepatocellular pattern of liver injury. Norethisterone was promptly discontinued, and anticoagulation therapy was initiated, the patient's symptoms improved significantly. This case highlights the importance of assessing thrombotic risk factors prior to prescribing norethisterone, especially in perimenopausal women, and emphasizes the need for vigilance regarding its potential vascular complications.
Deep vein thrombosis (DVT) is a condition characterized by the formation of a blood clot within the deep veins, more common in the lower limbs. It occurs due to a combination of factors known as Virchow’s triad, which includes venous stasis (reduced blood flow), endothelial injury (damage to the vessel lining), and hypercoagulable state (increased tendency of blood to clot) [1]. Several risk factors contribute to DVT, including prolonged immobility, recent surgery, trauma, obesity, malignancy, advanced age, smoking, pregnancy, and the use of hormonal therapies like norethisterone and other combined oral contraceptives. DVT is usually presents with unilateral leg swelling, pain, tenderness, warmth, and erythema, with some cases showing dilated superficial veins [3]. Diagnosis is usually confirmed through duplex ultrasonography, supported by D-dimer testing, with venography reserved for complex cases. Clinical management involves anticoagulation therapy using agents like low molecular weight heparin, direct oral anticoagulants, or warfarin, with thrombolytic therapy or inferior vena cava (IVC) filter placement considered in severe or contraindicated cases. Preventive measures include early mobilization after surgery, use of compression stockings, and thromboprophylaxis in high-risk patients. Assessing individual thrombotic risk is essential before prescribing medications like norethisterone, especially in perimenopausal women, to minimize the likelihood of DVT development [7]. Norethisterone is a synthetic progestogen derived from 19-nortestosterone, which is widely used in clinical trial for the management of various gynecological disorders. It acts by mimicking the actions of endogenous progesterone, exerting its effects primarily through binding to progesterone receptors, leading to secretory transformation of the endometrium, inhibition of ovulation at higher doses, and stabilization of the endometrial lining [4]. Clinically, norethisterone is prescribed for the treatment of menorrhagia, dysfunctional uterine bleeding, dysmenorrhea, endometriosis, premenstrual syndrome, and for postponement of menstruation. It is also used as hormone replacement therapy (HRT) in menopausal women to prevent endometrial hyperplasia when combined with estrogen. Norethisterone is available in oral tablet forms, typically in doses of 5 mg, 10 mg and 15mg with dosing regimens varies based on the indication [8]. Norethisterone-induced hepatic injury is a known adverse effect, may result from direct hepatotoxicity, hypersensitivity reactions, or cholestasis, Clinical symptoms of norethisterone-induced hepatitis can varies from mild transaminitis to severe liver damage [5]. Symptoms include jaundice, fatigue, and abdominal discomfort, which can likely be mistaken for other conditions. Hepatocellular liver injury remains rare and underreported. Early recognition and intervention are crucial to prevent serious complications. Estrogen has been more associated with liver injuries than progesterone. However only a few cases of progesterone induced liver injury have been reported [9]. In this case, aim to report drug induced deep vein thrombosis on left lower limb and elevated liver enzymes that occurred after administration of high doses of norethisterone for abnormal uterine bleed, in a patient without other identifiable thrombosis risk factors and hepatic injury.
Clinical Presentation:
A 49-years-old female patient with a medical history of acute heavy menstrual bleed, two weeks earlier she was started on norethisterone for bleeding (15mg orally twice daily for 7 days, then 15mg once daily for next 7 days). The bleeding was controlled. Within one week of completing norethisterone therapy, the patient developed pain and edema. The patient was now presented with complaints of pain, edema and swelling of left lower limb. The patient had no recent surgery, trauma, prolonged immobility and no family history of clotting disorder and hepatic disorders. On physical examination showed unilateral pitting edema and limb tenderness without signs of cellulitis. Homans’ sign was positive. A venous Doppler study of left lower limb revealed deep vein thrombosis of left femoral vein extending upto popliteal vein and extension of thrombus into the saphenofemoral junction and great saphenous vein upto the lower thigh. Other laboratory findings showed an elevation in AST of 217 U/L (normal range 15-37 U/L) and ALT of 313 U/L (normal range <50.0 U/L). USG abdomen showed impression of Fatty liver of Grade II, in addition, bilirubin, lipase, and amylase levels were within normal limit. The patient conditions were managed by the cessation of Norethisterone. To improve the blood flow and prevent blood clot T. RIVAROXABAN (20mg P/O 1-0-0), T. URSODEOXYCHOLIC ACID (300mg P/O 1-0-1) to prevent further liver damage T. ETORICOXIB (60mg P/O 1-0-0) to treat the pain and swelling.
DISCUSSION:
This case report highlights on a rare but significant occurrence of DVT induced by norethisterone in a 49-year-old woman being admitted for given norethisterone for menorrhagia. Norethisterone, a synthetic progestin commonly used for the management of menstrual disorders, is mostly reported with cholestatic derangement of liver enzymes. In here we report a case of norethisterone-induced DVT along with hepatotoxicity, a less commonly identified adverse effect in medical practice. The exact mechanism of action in which progestins alone trigger thrombosis is not clear. Estrogen is the main factor of clotting risk, but progesterones may also have some indirect effects on coagulation factors. This patient had no clotting disorder or estrogen exposure like no contraceptive pill or HRT. Her only apparent risk factors were age and recent hormone therapy. Age above 40 is itself a known risk factor for DVT and hormone exposure can affect the hemostatic balance. Diagnostic workup of suspected DVT depends on the clinical probability and imaging. In this case, venous Doppler ultrasound of the left lower limb confirmed the diagnosis. Several types of liver injuries like cholestatic injury, hepatitis and sinusoidal obstruction syndrome have been associated with female sex hormones or oral contraceptives. High doses of progestins may can lead to increase in liver enzymes normally within one to two weeks of treatment initiation, and usually manifest as ALT and AST elevations without elevations in alkaline phosphatase (ALP) or bilirubin. With dose modification or discontinuation of the therapy, these abnormalities normally resolves. In this patient she was previously diagnosed with Fatty Liver of Grade II in USG abdomen and there was a higher possible risk of having hepatic injury due to progestins. The exact mechanisms of action of progesterone-induced hepatic injury are not clearly identified. The only reported mechanism is the cholestatic jaundice occured with progesterone-only therapy that may be due to estrogenic compounds that can be the metabolites of semi-synthetic progesterone. In our patient, liver enzymes elevated within 2 weeks of therapy and gets back to normal after drug cessation, paralleling prior reports like example, a 62-year-old on 3 weeks of norethisterone (5 mg BID) who developed AST/ALT >15–20× baseline her enzymes normalized within ~2 weeks of stopping the drug [3]. The development of DVT after short-term norethisterone is rare but reported in at-risk women. Most literature involves other venous beds: Ramya et al. reported a 24-year-old with polycystic ovary syndrome (PCOS) they took norethisterone and developed cerebral venous sinus thrombosis (CVST). She was treated with low-molecular-weight heparin followed by warfarin and had a complete cure [11]. Similar cases like, Saxena et al. described a 45-year-old on high-dose norethisterone (30 mg/day) who developed extensive portal vein thrombosis (with bowel ischemia). She received rivaroxaban 15 mg twice daily and improved by day 7 symptoms were resolving and a day 12 Doppler showed thrombus recanalization. These cases (CVST and portal vein thrombosis) underscore that norethisterone can rarely precipitate serious clots, especially early in therapy [12]. This case summarises progestin-only treatment can possibly lead to thrombosis and worsen liver functions. Physicians should counsel VTE risk when prescribing high-dose norethisterone, specifically in gediatric or immobilized patients. Alternatives for AUB include levonorgestrel IUDs or tranexamic acid, which can lower the clotting risks. If progestins only are prescribed then the patients should be informed about DVT symptoms, liver toxicity and other possible reactions that can be occurred.
CONCLUSION:
This case report weight the importance of significant occurrence of DVT on hormone therapy in patient with fatty liver. This case focuses on the need of monitoring liver function tests (LFTs) when initiating norethisterone therapy and careful risk assessment. Early identification of symptoms, discontinuation of the responsible agent, and appropriate medical intervention are essential parts to prevent severe complications. This report focuses on the importance of individualized patient evaluation and vigilant monitoring when initiating norethisterone therapy, particularly in perimenopausal women with hepatic complications.
REFERENCES
Rahil S. K., Nizi Alexander, Dr. Reshma Babu*, Dr. Shaiju Dharan, Norethisterone Induced Deep Vein Thrombosis and Hepatotoxicity: A Case Report, Int. J. of Pharm. Sci., 2025, Vol 3, Issue 7, 1170-1174. https://doi.org/10.5281/zenodo.15844765